The present patent application relates to new substituted 3-phenoxy- or 3-phenylalkyloxy-2-phenyl-propylamines of general formula 1, processes for preparing them and their use as pharmaceutical compositions. 
wherein
R1 and R2 independently of one another may denote hydrogen, C1-C8-alkyl, benzyl, furylmethyl, cycloalkyl, cycloalkyl-methyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy-(CH2)1xe2x80x94, C3-C8-cycloalkoxy-(CH2)mxe2x80x94 and
1 may denote an integer 1, 2, 3, 4, 5, 6, 7 or 8 and
m may denote an integer 0, 1, 2, 3, 4, 5, 6, 7 or 8 or
R1 and R2 together with the nitrogen atom form a 3-, 4-, 5-, 6-, 7- or 8-membered heterocyclic ring which may optionally be substituted with 1-4 methyl groups or a dimethylene group; or
R1 and R2 together may denote a xe2x80x94CH2xe2x80x94(CHxe2x95x90CH)xe2x80x94(CH2)2-bridge;
n may denote an integer 0, 1, 2 or 3;
R3, R3xe2x80x2, R4 and R4xe2x80x2 independently of one another may denote hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, ethyl, methoxy or CF3;
R5 and R6 independently of one another may denote hydrogen, fluorine, chlorine, bromine, methyl, ethyl or CF3 or
R5 and R6 adjacent to each other may denote a fused-on aromatic ring;
R7 may denote hydrogen, fluorine, chlorine, methyl, ethyl, methoxy or an aromatic ring fused on at the free vicinal position;
R8 may denote hydrogen, fluorine, chlorine, methyl, ethyl or methoxy.
Preferred compounds of general formula 1 are those wherein
R1 and R2 independently of one another may denote hydrogen, C1-C6-alkyl, benzyl, furylmethyl, cycloalkyl, cycloalkyl-methyl, C2-6-alkenyl, preferably allyl, C2-C6-alkynyl, preferably propargyl, C1-C6-alkoxy-(CH2)1xe2x80x94, C3-8-cycloalkoxy-(CH2)mxe2x80x94 and
1 denotes an integer 1, 2, 3 or 4, and
m denotes an integer 0, 1, 2, 3 or 4, or
R1 and R2 together with the nitrogen atom form a 5-, 6-, or 7-membered heterocyclic ring, which may optionally be substituted with 1-4 methyl groups or a dimethylene group;
n may denote an integer 0, 1, 2 or 3;
R3, R4 and R3xe2x80x2 independently of one another may denote hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, ethyl, methoxy or CF3;
R4xe2x80x2 may denote hydrogen;
R5 and R6 independently of one another may denote hydrogen, fluorine, chlorine, bromine, methyl or ethyl or
R5 and R6 adjacent to one another denote a fused-on aromatic ring;
R7 and R8 independently of one another may denote hydrogen, methyl, ethyl, methoxy or fluorine.
Particularly preferred are the compounds of general formula 1, wherein:
R1 and R2 independently of one another may denote hydrogen, C1-C6-alkyl, benzyl, furylmethyl, cycloalkyl, cycloalkyl-methyl, C2-C6-alkenyl, preferably allyl, C2-6-alkynyl, preferably propargyl, C1-6-alkoxy-(CH2)1xe2x80x94, C3-8-cycloalkoxy-(CH2)mxe2x80x94, and
1 denotes an integer 1, 2, 3 or 4, and
m denotes an integer 0, 1, 2, 3 or 4, or
R1 and R2 together with the nitrogen atom form a 5-, 6-, or 7-membered heterocyclic ring, which may optionally be substituted with 1-4 methyl groups or a dimethylene group;
n may denote an integer 0, 1, 2 or 3;
R3 and R4 independently of one another may denote hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, ethyl, methoxy or CF3;
R3xe2x80x2 and R4xe2x80x2 may denote hydrogen;
R5 and R6 independently of one another may denote hydrogen, fluorine, chlorine, bromine, methyl or ethyl;
R7 and R8 independently of one another may denote hydrogen, methyl, ethyl, methoxy or fluorine.
Of particular interest according to the invention are compounds of general formula 1, wherein:
R1 and R2 independently of one another denote hydrogen, C1-4-alkyl, benzyl, furylmethyl, cycloalkyl, cycloalkyl-methyl, C2-4-alkenyl, preferably allyl, C2-C4-alkynyl, preferably propargyl, C1-C4-alkoxy-(CH2)1xe2x80x94, C3-C6-cycloalkoxy-(CH2)mxe2x80x94 and
1 denotes an integer 1, 2 or 3, and
m denotes an integer 1, 2 or 3, or
R1 and R2together with the nitrogen atom form a 5- or 6-membered heterocyclic ring which may optionally be substituted with 1, 2 or 3 methyl groups or a dimethylene group;
n may denote an integer 0, 1, 2 or 3;
R3 may denote fluorine, chlorine or methyl, preferably in the ortho position;
R4 may denote hydrogen, fluorine, chlorine or methyl, preferably in the ortho position;
R3xe2x80x2 and R4xe2x80x2 may denote hydrogen;
R5 and R6 independently of one another may denote hydrogen or methyl;
R7 and R8 independently of one another may denote methyl, ethyl or methoxy.
Most particularly preferred are compounds of general formula 1, wherein
R1 and R2 independently of one another denote hydrogen, methyl, ethyl, propyl, butyl, benzyl, furylmethyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, C2-C4-alkenyl, preferably allyl, C2-C4-alkynyl, preferably propargyl, C1-C4-alkoxy-(CH2)1xe2x80x94, C3-C6-cycloalkoxy-(CH2)mxe2x80x94, and
1 denotes an integer 1, 2 or 3 and
m denotes an integer 1, 2 or 3, or
R1 and R2together with the nitrogen atom form a 5- or 6-membered heterocyclic ring which may optionally be substituted with 1 or 2 methyl groups or a dimethylene group;
n may denote 1;
R3 may denote ortho-fluorine, ortho-chlorine or ortho-methyl;
R4 may denote hydrogen, ortho-fluorine, ortho-chlorine or ortho-methyl;
R3xe2x80x2 and R4xe2x80x2 may denote hydrogen;
R5 and R6 may denote hydrogen;
R7 and R8, which may be identical or different, may denote methyl or ethyl, preferably methyl.
The following compounds are mentioned as examples of compounds of particular interest according to the invention:
N-Pentamethylene-3-(2,6-difluorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine;
N-Pentamethylene-3-(2-fluorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine;
N-Pentamethylene-3-(2,6-dichlorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine;
N-Pentamethylene-3-(2,6-dimethylphenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine;
N-Cyclopropylmethyl-3-(2,6-difluorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine;
N-Allyl-3-(2,6-difluorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine;
N-(3,3-Dimethylallyl)-3-(2,6-difluorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine;
N-(2-Methylallyl)-3-(2,6-difluorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine;
N-(1-Methylallyl)-3-(2,6-difluorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine.
The invention relates to the compounds in question, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates and in the form of the free bases or the corresponding acid addition salts thereof with pharmacologically acceptable acidsxe2x80x94such as for example acid addition salts with hydrohalic acidsxe2x80x94e.g. hydrochloric or hydrobromic acidxe2x80x94or organic acidsxe2x80x94such as e.g. oxalic, fumaric or diglycolic acid or methanesulphonic acid.
Unless otherwise stated, the general definitions are used as follows:
C1-C4-alkyl or C1-C8-alkyl generally denotes a branched or unbranched hydrocarbon group having 1 to 4 carbon atom(s), which may optionally be substituted with one or more halogen atomsxe2x80x94preferably fluorinexe2x80x94, which may be identical to or different from one another. The following hydrocarbon groups are mentioned by way of example:
methyl, ethyl, propyl, 1-methylethyl(isopropyl), n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2,-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise specified, the preferred groups are lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl. The definitions propyl, butyl, pentyl, etc., always include the isomeric groups in question.
Accordingly, alkylene denotes a branched or unbranched double-bonded hydrocarbon bridge with 1 to 8 carbon atoms which may optionally be substituted by one or more halogen atom(s)xe2x80x94preferably fluorinexe2x80x94which may be identical to or different from each other.
Cycloalkyl generally represents a saturated or unsaturated cyclic hydrocarbon group with 3 to 9 carbon atoms, which may optionally be substituted with one or more halogen atomsxe2x80x94preferably fluorinexe2x80x94which may be identical to or different from each other. Cyclic hydrocarbons with 3 to 6 carbon atoms are preferred. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl and cyclononinyl.
Alkenyl is generally a branched or unbranched hydrocarbon group with 2 to 8 carbon atoms which may contain one or more double bonds and which may optionally be substituted by one or more halogen atomsxe2x80x94preferably fluorinexe2x80x94whilst the halogens may be identical or different. The following alkenyl groups are mentioned by way of example:
vinyl, 2-propenyl (allyl), 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl.
Of the lower alkenyl groups which have three or four carbon atoms and a double bond, the allyl group is preferred.
Alkynyl generally denotes a branched or unbranched hydrocarbon group with 2 to 8 carbon atoms which may have one or more triple bonds and may optionally be substituted by one or more halogen atomsxe2x80x94preferably fluorinexe2x80x94, whilst the halogens may be identical or different. The following alkynyl groups are mentioned by way of example:
2-propynyl(propargyl), 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 3-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1,2-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-methyl-2-pentynyl, 4-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 3-methyl-3-pentynyl, 4-methyl-3-pentynyl, 1-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-4-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-2-butynyl, 1,2-dimethyl-3-butynyl, 1,3-dimethyl-2-butynyl, 1,3-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 2,3-dimethyl-2-butynyl, 2,3-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-1-butynyl, 2-ethyl-2-butynyl, 2-ethyl-3-butynyl, 1,1,2-trimethyl-2-propynyl, 1-ethyl-1-methyl-2-propynyl and 1-ethyl-2-methyl-2-propynyl.
Of the lower alkynyl groups which have three or four carbon atoms and a triple bond, the propargyl group is preferred.
Alkoxy generally denotes a straight-chained or branched hydrocarbon group bound via an oxygen atomxe2x80x94a lower alkoxy group with 1 to 4 carbon atom(s) is preferred. The methoxy group is particularly preferred.
A fused-on aromatic ring, unless otherwise defined, denotes a fused-on benzene ring, for the purposes of the invention.
Biological Properties
The compounds claimed are blockers of the voltage-dependent sodium channel. These are compounds which displace batrachotoxin (BTX) with a high affinity (Ki  less than 1000 nM) competitively or non-competitively from the binding site on the sodium channel. Such substances exhibit xe2x80x9cuse-dependencyxe2x80x9d while the sodium channels are blocked, i.e. in order to bind the substances at the sodium channel, the sodium channels first have to be activated. Maximum blockage of the sodium channels is only achieved after repeated stimulation of the sodium channels. Consequently, the substances bind preferentially to sodium channels which are activated a number of times. As a result, the substances are in a position to become effective particularly in those parts of the body which are pathologically overstimulated. The compounds of general formula 1 according to the invention can thus be used to treat diseases which are caused by a functional disorder resulting from overstimulation. These include diseases such as arrhythmias, spasms, cardiac and cerebral ischaemias, pain neurodegenerative diseases of various origins. These include, for example: epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, cerebral strokes perinatal asphyxia, degeneration of the cerebellum, amyotropic lateral sclerosis, Huntington""s disease, Alzheimer""s disease, Parkinson""s disease, cyclophrenia, hypotonia, cardiac infarction, heart rhythm disorders, angina pectoris, chronic pain, neuropathic pain and local anaesthesia.
The blocking action on the sodium channel may be demonstrated by the test system which tests the BTX binding to the sodium channel [S.W. Postma and W. A. Catterall, Mol. Pharmacol 25, 219-227 (1984)] as well as by patch-clamp experiments which show that the compounds according to the invention block the electrically stimulated sodium channel in a xe2x80x9cuse-dependentxe2x80x9d manner [W. A. Catterall, Trends Pharmacol. Sci., 8, 57-65 (1987)]. By a suitable choice of cell system (e.g. neuronal, cardiac, DRG cells) it is possible to test the effect of the substances on different subtypes of sodium channel.
The sodium channel blocking property of the compounds according to the invention can be demonstrated by the blocking of the veratridine-induced release of glutamate [S. Villanueva, P. Frenz, Y. Dragnic, F. Orrego, Brain Res. 461, 377-380 (1988)]. Veratridine is a toxin which opens the sodium channel permanently. This leads to an increased influx of sodium ions into the cell. By means of the cascade described above, this sodium influx leads to increased release of glutamate in the neuronal tissue. The compounds according to the invention antagonise this release of glutamate.
The anticonvulsant properties of the substances according to the invention were demonstrated by their protective effect against convulsions triggered by a maximum electric shock in mice [M. A. Rogawski and R. J. Porter, Pharmacol. Rev. 42, 223-286 (1990)].
Neuroprotective properties were demonstrated by a protective effect in a rat MCAO model [U. Pschorn and A. J. Carter, J. Stroke, Cerebrovascular Diseases, 6, 93-99 (1996)] and a malonate-induced lesion model [M. F. Beal, Annals of Neurology, 38, 357-366 (1995) and J. B. Schulz, R. T. Matthews, D. R. Henshaw and M. F. Beal, Neuroscience, 71, 1043-1048 (1996)].
Analgesic effects can be investigated in models of diabetic neuropathy and in a ligature model [C. Courteix, M. Bardin, C. Chantelauze, J. Lavarenne, A. Eschalier, Pain 57, 153-160 (1994); C. Courteix, A. Eschalier, J. Lavarenne, Pain 53, 81-88 (1993); G. J. Bennett and Y.-K. Xie, Pain 33, 87-107 (1988)].
It has also been reported that sodium channel blockers can be used to treat cyclophrenia (manic depressive disorder) [J. R. Calabrese, C. Bowden, M. J. Woyshville; in: Psychopharmacology: The Fourth Generation of Progress (Eds.: D. E. Bloom and D. J. Kupfer) 1099-1111. New York: Raven Press Ltd.].
Methods of Preparation
The claimed compounds 1 can be prepared by methods known from the prior art. One possible method of synthesis is shown in Diagram 1. The starting compounds are the substituted benzylcyanides of the type of general formula 2. Benzylcyanide derivatives of this kindxe2x80x94such as e.g. 2,6-dimethylbenzylcyanides of general formula 2 and their preparation are described in the literature [e.g. Bennett et al., J. Med. Chem. 24, 382-389 (1981); Benington et al. J. Org. Chem. 23, 2034-2035 (1958); Carlin et al. J. Org. Chem. 30, 563-566 (1965)], or may be prepared analogously by these methods.
Diagram 1 (the N protecting group SG is shown here as a BOC protecting group, for example): 
The 2,6-substituted benzylcyanide derivatives of general formula 2 are reacted after deprotonation with formic acid esters, preferably with ethyl formate. The deprotonation may be carried out with any suitable base known from the prior art. Preferably, alkali organyls are used as organometallic bases, particularly alkali metal alkoxides; it is particularly preferable to use potassium tert. butoxide for the deprotonation. The reaction media used may be any aprotic solvents which are inert under the reaction conditions specified and which are suitable for the reaction of deprotonation from the point of view of their physical parameters. Aliphatic or aromatic hydrocarbons in particular are used as solvent, of whichxe2x80x94optionally alkyl-substitutedxe2x80x94aromatic compounds are preferred; it is particularly preferably to use toluene as reaction medium. The reaction temperature is within a range which is not so low as to make the desired deprotonation difficult or impossible, on the one hand, but it not in a range which makes it possible for side reactions or subsequent reactions to occur. Depending on the particular solvent used a temperature in the range from xe2x88x9220 to +30xc2x0 C. xe2x80x94preferably in the range from xe2x80x9410 to 20xc2x0 C. and most preferably in the range from xe2x88x9210 to xe2x88x925xc2x0 C. xe2x80x94will be selected, whilst the reaction mixture should appropriately be left to finish reacting at ambient temperature (about 0 to 30xc2x0 C.). After the hydrolysis has ended the reaction product of type 3 is isolated by extraction, for example, and optionally purified by standard methods known from the prior art, preferably by recrystallisation.
Then the formyl group is reduced to the alcohol of general formula 4 and the nitrile 4 is then reduced to the amine 5. The reduction of the formyl group to the corresponding alcohol well known from the prior art [J. March, Advanced Organic Chemistry, Wiley Interscience, New York (1989), 4th edition, page 910 ff.; C Larock, Comprehensive Organic Transformations, VCH Publishers Inc., New York (1989), p. 527 ff and cit. lit.]. Preferably the reduction is carried out with complex hydridesxe2x80x94such as e.g. with complex alkali boron hydrides or alkali aluminium hydrides or optionally with suitable derivatives thereof, the use of sodium cyanoborohydride being particularly preferred. It is usually advisable to carry out such reductions in the presence of an excess of reduction agent which is preferably one of the abovementioned hydrides, which is in the range from 5 to 100% and preferably in the range from 50 to 100% and most preferably in the range from 70 to 90%. Suitable reaction media are any solvents which do not have a deleterious effect on the course of the reaction. Solvents of this kind are sufficiently well known from the prior art; preferably, branched or unbranched alcohols, particularly lower C1-C4-alkanols, are used, of which methanol is particularly preferred. The reduction may be carried out within a wide temperature range, the choice of temperature being guided particularly by the activity of the complex hydride used, as well as the physical parameters of the reaction medium. The reduction product 4 is isolated, after the destruction of excess reduction agent, in a manner known from the prior artxe2x80x94particularly by extraction.
The reduction of the nitrile 4 thus obtained to the corresponding amine is also known per se from the prior art [J. March, Advanced Organic Chemistry, Wiley Interscience, New York (1985), 3rd edition, pp. 815 ff.; C. Larock, Comprehensive Organic Transformations, VCH Publishers Inc., New York (1989), p. 437 ff. and cit. lit.; P. N. Rylander: Hydrogenation Methods, Academic Press, New York (1985), Chapter 7]. According to the invention, catalytic reduction with hydrogen in the presence of Raney nickel in the presence of an aminexe2x80x94preferably in the presence of ammoniaxe2x80x94is preferred. The reaction medium used for the reduction may be any solvent which does not have a detrimental effect on the course of the reaction or, particularly, the activity of the catalyst. Solvents of this kind are known in sufficient numbers from the prior art; preferably, branched or unbranched alcoholsxe2x80x94particularly lower C1-C4-alkanolsxe2x80x94are used, methanol being particularly preferred. The other parameters of the reaction of reduction may be varied within wide limits and are dependent not only on the educt but particularly on the activity of the Raney nickel which is preferably used. Preferably, the reduction is carried out under a hydrogen pressure in the range from 10 to 200 bar, a hydrogen pressure of 70 bar being particularly preferred. The reaction temperature may be selected within the range from 20 to 150xc2x0 C.xe2x80x94the reduction is most preferably carried out at 70xc2x0 C. After the reduction is completed and optionally after the reaction mixture has been cooled, the catalyst is filtered off and the filtrate is purified by methods known from the prior artxe2x80x94wherever possible by distillation (under high vacuum).
At the stage of the aminoalcohol 5 the racemate may optionally be cleaved into the enantiomers. The subsequent cleaving of the resulting mixture of the enantiomeric aminoalcohols of type 5 may be carried out by the methods of enantiomer separation known per se from the prior artxe2x80x94for example by reaction with malic acid, tartaric acid, mandelic acid or camphorsulphonic acid, tartaric acid being particularly preferred.
Thus, for example, reaction with S-(xe2x88x92)-tartaric acid in the case of 3-hydroxy-2-(2,6-dimethylphenyl)-propylamine yields the corresponding enantiomerically pure aminoalcohol of type 5a in the form of its hydrogen tartrate; analogously, the corresponding reaction with R-(+)-tartaric acid yields the enantiomerically pure aminoalcohol of type 5b.
For isomer separationxe2x80x94for example via the corresponding tartratesxe2x80x94the aminoalcohol 5 xe2x80x94for example in the form of the free basexe2x80x94is dissolved in a branched or unbranched C1-C4-alkanol, most preferably in methanolxe2x80x94and combined with the appropriate stereoisomers of one of the abovementioned acids, for example D-(xe2x88x92)-tartaric acid. If necessary a sufficient amount of a nonsolvent with regard to the desired saltxe2x80x94preferably the corresponding hydrogen tartratexe2x80x94is added, after which the enantiomerically pure isomer of the aminoalcohol 5 crystallises out as the hydrogen tartrate which can be further purified, if necessary, by recrystallisation.
The racemic or enantiomerically pure aminoalcohol 5 or 5a or 5b is reacted in the next step with a compound of type X-S, wherein X denotes a leaving group which can be substituted by an aminonitrogen and S denotes a protecting group suitable for protecting primary amines. Such reagents and methods of binding amine protecting groups thereto are known in large numbers from the prior art [T. W. Greene and P. G. M. Wuts: Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., New York (1991), p. 309 ff.]. According to the invention, in the present instance, the aminonitrogen is preferably selectively N-protected using di-tert.-butyl pyrocarbonate. For this, the racemic or enantiomerically pure aminoalcohol of type 5 or 5a or 5b is dissolved in a solvent which is inert under the reaction conditions specified. Suitable solvents are preferably lower alkyl esters of lower carboxylic acids, of which ethyl acetate is particularly preferred. The reaction with di-tert.-butyl pyrocarbonate is preferably carried out in the temperature range from xe2x88x9220 to 75xc2x0 C. and most preferably in the range from xe2x88x9210 to +25xc2x0 C. After the reaction has taken place the solvent is eliminated, the residue is mixed with an aqueous solution of an acidically reacting compound, preferably 90% acetic acid. After about one hour the reaction mixture is evaporated down and the residue is taken up in a suitable solvent, preferably with a lower alkyl ester of a lower carboxylic acid and most preferably with ethyl acetate and after washing with a basically reacting washing solutionxe2x80x94preferably with aqueous ammonia solutionxe2x80x94the solvent is eliminated.
Then, the alcohol function in the N-protected aminoalcohol of type 6, in the alkaline range, is reacted with correspondingly substituted phenylalkylhalides, resulting in the desired ether structures of general formula 7. The reaction of alcohols of type 6 with phenylalkylhalidesxe2x80x94particularly with benzylhalidesxe2x80x94is well known from the prior art [C. Larock, Comprehensive Organic Transformations, VCH Publishers Inc., New York, Weinheim (1989), p. 446 ff. and cit. lit.].
In order to prepare the aminoethers of type 7 , for example, the protected aminoalcohol of general formula 6 is dissolved in a suitable solvent which is inert under the reaction conditions chosen. Suitable reaction media for carrying out the reaction according to the invention are halogenated lower hydrocarbons, of which halogenated C1- or C2-alkanes are preferred, whilst methylene chloride (dichloromethane) is most preferred as the reaction medium. In the choice of the abovementioned solvent, the use of a phase transfer catalyst has proved particularly advantageous. Phase transfer catalysts of this kind are known in sufficient numbers from the prior art [Rxc3x6mpp, Lexikon Chemie, Georg Thieme Verlag, Stuttgart (1998)]. In the preparation of the compounds according to the invention, so-called tetraalkylammonium compounds have proved particularly suitable. Phase transfer catalysts of this kind according to the invention are quaternary ammonium compounds of type [R4N]+Xxe2x80x94 wherein the substituents R, which may be identical or different, are preferably lower alkyl groups. According to the invention, tetrabutylammonium salts are most preferred, of which tetra-n-butylammonium hydrogen sulphate is most preferred.
The aqueous phase used is preferably an aqueous solution of a basically reacting compound of an alkali metal or alkaline earth metal. It is preferable to use an aqueous solution of an alkali metal hydroxide, 50% aqueous sodium hydroxide solution being most preferred.
The reaction with the phenylalkyl derivative, preferably with a phenylalkylhalide and most preferably with a phenylalkylbromide, may be carried out within a wide temperature range the lower limit of which is determined by the reactivity of the reactants and the upper limit of which is determined by the boiling point of the solvent used. Preferably, the reaction of substitution is carried out at a temperature in the range from +5 to 60xc2x0 C. and most preferably at 0 to 30xc2x0 C. (which corresponds to ambient temperature for the purposes of the present invention).
After the reaction the organic phase is separated off and the aqueous phase is extracted exhaustively with a suitable solventxe2x80x94preferably with a halogenated lower hydrocarbon, of which halogenated C1- or C2-alkanes are most preferred, and most preferably with methylene chloride. The combined organic phases are then washed with the aqueous solution of an acidically reacting compound, preferably with the aqueous solution of an inorganic acid and most preferably with 2 N hydrochloric acid, dried and concentrated by evaporation. The residue can then be further purified by methods known per se from the prior artxe2x80x94particularly by crystallisation.
After the protecting group has been cleaved with HCl gas the groups R1 and R2 can then be introduced selectively by alkylation, reductive amination or acylation and subsequent reduction.
For cleaving the protecting group from the aminonitrogen, it should be noted that this is also known from the prior art [T. W. Greene and P. G. M. Wuts: Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., New York (1991), p. 309 ff.]. The subsequent introduction of the groups R1 and R2 at the amino function may take place on the one hand within the scope of an acylation with subsequent reduction. The required carboxylic acid derivatives for this purpose are either known from the prior art or are readily obtained using current methods of synthesis [Houben-Weyl: Methoden der organischen Chemie, volume VIII and volume E5, Georg Thieme Verlag, Stuttgart 1952 or 1985].
For the acylation itself there are a number of methods to choose from [C. Ferri: Reaktionen der organischen Synthese, Georg Thieme Verlag, Stuttgart (1978), p.222 ff. and cit. lit; J. March, Advanced Organic Chemistry, 3rd Edition., John Wiley and Sons, New York 1985, p. 370 ff. and cit. lit.; R. C. Larock, Comprehensive Organic Transformationxe2x80x94A Guide to Functional Group Preparations, VCH Verlagsgesellschaft, Weinheim (1989), p. 963 ff. and cit. lit.], whilst reactions with carboxylic acid halides in a solvent which is substantially inert under the prevailing reaction conditionsxe2x80x94optionally in the presence of acid-binding agentsxe2x80x94such as e.g.: tertiary amines or alkali metal or alkaline earth metal saltsxe2x80x94are preferred [A. L. J. Beckwith in J. Zabicki: The Chemistry of Amides, Interscience, New York (1970), p. 73 ff.]. The inert solvents used are generally organic solvents which do not change under the reaction conditions used, such as e.g.: hydrocarbonsxe2x80x94for example benzene, toluene, xylene or petroleum fractionsxe2x80x94or ethersxe2x80x94such as e.g.: diethylether, glycoldimethylether (glyme), diglycoldimethylether (diglyme)xe2x80x94or cyclic ethersxe2x80x94such as e.g.: tetrahydrofuran (THF), or dioxanexe2x80x94or halogenated hydrocarbonsxe2x80x94such as for example dichloromethane (methylene chloride).
Conveniently, the aminoether of general formula 8 is preferably reacted in halogenated hydrocarbonsxe2x80x94most preferably in THFxe2x80x94in the presence of acid-binding alkali metal or alkaline earth metal carbonates, most preferably in the presence of potassium carbonate, with the desired acid halides, preferably with the corresponding acid chloride.
However, it is also possible to perform the reactionxe2x80x94in accordance with the so-called Schotten-Baumann variantxe2x80x94in water or in an aqueous alcohol in the presence of alkali metal hydroxides or alkali metal carbonates [Organikum, Organisch-chemisches Grundpraktikum, 19th edition, Johann Ambrosius Barth, Leipzig, Edition Deutscher Verlag der Wissenschaften (1993), p. 424]. Depending on the educts used, it may also prove advantageous to carry out the acylation by the Einhorn variant [Organikum, Organisch-chemisches Grundpraktikum, 19th edition, Johann Ambrosius Barth, Leipzig, Edition Deutscher Verlag der Wissenschaften (1993), p. 424], whilst pyridine is used both as the acid-binding agent and as the reaction medium.
It is also possible to perform the reaction of acylation with the relevant free carboxylic acid [A. L. J. Beckwith in J. Zabicki,: The Chemistry of Amides, Interscience, New York (1970), p. 105 ff.; J. A. Mitchell and E. E. Reid, J. Am. Chem. Soc. 53, (1931) 1879].xe2x80x94It may also prove advantageous to use a mixed anhydridexe2x80x94e.g. with a carbonic acid ester [C. Ferri: Reaktionen der organischen Synthese, Georg Thieme Verlag, Stuttgart (1978), p.222 ff. and cit. lit.; A. L. J. Beckwith in J. Zabicki,: The Chemistry of Amides, Interscience, New York (1970), p. 86 ff.; J. March, Advanced Organic Chemistry, 3rd Edition., John Wiley and Sons, New York 1985, p. 371 and cit. lit.; R. C. Larock, Comprehensive Organic Transformationsxe2x80x94A Guide to Functional Group Preparations, VCH Verlagsgesellschaft, Weinheim (1989), p. 981 ff. and cit. lit.].
During the preferred acylation with carboxylic acid halidesxe2x80x94particularly with carboxylic acid chloridesxe2x80x94the reaction temperature may vary within wide limits, the lower limit being set by too slow a reaction speed and the upper limit being set by the proliferation of undesirable side reactions. In practice, reaction temperatures in the range from xe2x88x9250 to 150xc2x0 C. and preferably in the range from 0 to 75xc2x0 C. have proved satisfactory, the reaction temperature chosen naturally being guided by the solvent used. Suitable solvents are, primarily, inert solvents which do not have a detrimental effect on the reaction of acylation. These include mainly ethersxe2x80x94such as e.g.: diethylether, glycoldimethylether (Glyme), diglycoldimethylether (Diglyme)xe2x80x94or cyclic ethersxe2x80x94such as e.g.: tetrahydrofuran (THF), or dioxane, whilst THF is most preferred. The process is usefully carried out with a small excess of the acylating agent in the presence of an acid-binding agentxe2x80x94present in a somewhat greater excessxe2x80x94to ensure the maximum possible reaction of the educts.
In order to obtain the desired aminoether of general formula 1, it is necessary in the last analysis to reduce the resulting acid amide in the subsequent reaction step.xe2x80x94Reductions of acid amides of this kind are also well known from the prior art and may be carried out both by electrolytic reduction, by reduction with alkali metals and by catalytic reduction [R. Schrxc3x6ter in Houben-Weyl: Methoden der organischen Chemie, volume XI/1 and volume E5, Georg Thieme Verlag, Stuttgart 1957, p. 574] or with diborane or hydrogen boride derivatives [J. Furhop and G. Penzlin, Organic Synthesisxe2x80x94Conceptsxe2x80x94Methodsxe2x80x94Starting Materialsxe2x80x94, VCH-Verlagsgesellschaft, Weinheim 1986, p. 90.
However, reduction with complex hydrides, such as alkali boron or alkali aluminium hydrides or with suitable derivatives thereofxe2x80x94optionally in the presence of a catalystxe2x80x94[N.G. Gaylord: Reduction with Complex Metal hydrides, Wiley, New York (1965); A. Hàjos: Complex hydrides, Elsevier, New York (1979); V. Bazant, M. Capka, M. Cerny, V. Chvalovsky, K. Kochloefl, M. Kraus um M. Màlek, tetrahedron Lett. 9 (1986) 3303] is preferred, the use of lithium aluminium hydride being most preferred.
Suitable reaction media are any inert organic solvents which do not change under the reaction conditions specified. These include ethersxe2x80x94such as for example diethylether, diisopropylether, glycoldimethylether (Glyme), diglycoldimethylether (Diglyme)xe2x80x94or cyclic xe2x80x94ethersxe2x80x94such as e.g.: tetrahydrofuran (THF), or dioxane, of which THF is most preferred, the choice of reaction medium depending inter alia on the nature of the reduction agent used.
When carrying out the reaction it is generally advantageous to perform such reductions in the presence of an excess of the reduction agent, which is preferably one of the abovementioned complex hydridesxe2x80x94particularly lithium tetrahydridoalanatexe2x80x94which is in the range from 5 to 100%xe2x80x94preferably in the range from 10 to 50%. The reactants are normally added while cooling with ice or at ambient temperature and then heated to a reaction temperature in the range from 50 to 150xc2x0 C., depending on the reactivity of the educts.
Another possible method of preparing the aminoethers of general formula 1 according to the invention from the precursor 8 comprises reacting the amine of type 8 with suitable alkylating agents. These alkylating agents of type R1xe2x80x94Z or R2xe2x80x94Z should conveniently have a suitable leaving group which may be substituted by the amino-nitrogen. Examples of preferred leaving groups of type Z are halogensxe2x80x94such as preferably chlorine, bromine or iodinexe2x80x94or xe2x80x94Oxe2x80x94SO2-arylxe2x80x94such as e.g.: tosylatexe2x80x94or an alkylsulphonate of type xe2x80x94Oxe2x80x94SO2-alkylxe2x80x94such as e.g.: methanesulphonate or halomethanesulphonate or sulphate.xe2x80x94Corresponding alkylating agents are either commercially obtainable or their preparation is known from the prior art.
Suitable solvents are any inert solvents which do not change substantially under the reaction conditions specified and which cannot themselves have a detrimental effect on the course of the reaction as reactive components. These preferably include ethers, such as for example diethylether, diisopropylether, glycoldimethylether (Glyme), diglycoldimethylether (Diglyme), or cyclic ethers, such as e.g.: tetrahydrofuran (THF), or dioxane, or ketones, such as e.g.: methylethylketone or acetone, or acid amides, such as hexamethylphosphotriamide or dimethylformamide (DMF).
It is also possible to use mixtures of the abovementioned solvents. It is particularly preferred to use THF or dimethylformamide (DMF). The reaction of alkylation is preferably carried out in the presence of acid-binding agents, such as e.g.: alkali metal or alkaline earth metal carbonates or hydrogen carbonates.
The reaction temperature may vary within wide limits in the course of the reaction, the lower limit being determined by too slow a reaction speed and the upper limit being determined by the proliferation of side reactions, in practical terms, apart from the corresponding physical values of the solvents. Suitable reaction temperatures are in the range from 0 to 150xc2x0 C. and, preferably, between 50 and 100xc2x0 C.
It is also possible to introduce the desired substituents at the amino function by reductive amination [Organikum, Organisch-chemisches Grundpraktikum, 19th edition, Johann Ambrosius Barth, Leipzig, Edition Deutscher Verlag der Wissenschaften (1993), p. 451; [C. Ferri: Reaktionen der organischen Synthese, Georg Thieme Verlag, Stuttgart (1978), p.85 ff.]xe2x80x94for example by a Leuckard-Wallach reaction or amination according to Decker/Forster [H. Krauch and W. Kunz, Reaktionen der organischen Chemie, Hxc3xcthig Verlag, Heidelberg (1997) p. 104 ff.] and thus arrive at the aminoethers of general formula 1.
During catalytic reductive amination, Raney nickel, optionally doped with other elementsxe2x80x94such as e.g. chromiumxe2x80x94is generally used. In addition, the reductive amination may also be carried out in the presence of a platinum catalyst, which normally makes it possible to perform the reaction under milder conditions. In general the catalytic reductive amination is performed in the temperature range from 20 to 160xc2x0 C. The temperature to be adopted depends essentially on the activity of the catalyst, and the reactivity of the amine and carbonyl component. The first choice of solvents will be alcohols or water, lower alcoholsxe2x80x94such as methanol, ethanol or isopropanolxe2x80x94being preferred; most preferably, methanol is used as the solvent. The hydrogen pressure may also vary within a wide range and is generally in the range from 1 to 100 atmospheres (1.01 to 101.33 bar), preferably 5 to 80 atmospheres (5.07 to 81.06 bar).
Alternatively, the claimed compounds 1 wherein R1 and R2=xe2x80x94(CH2)mxe2x80x94 (where m preferably denotes 5 or 6) may be prepared by the method illustrated in Diagram 2.
Diagram 2: 
The 3-step reaction sequence may be carried out by the use of racemic epichlorohydrin or R- or S-epichlorohydrin either racemically or stereospecifically - analogously to the methods known from the prior art [J. Amer. Chem. Soc. 80 (1958) 1257]. The amino-oxirane intermediates 9 are appropriately purified by distillation or by flash chromatography, however, they may also be further processed direct s crude products. The intermediate 10a is generated by Grignard reaction and conveniently separated from the unwanted regioisomer 10b by chromatography. The regioisomer ratio can be shifted in favour of 10a if the aminooxirane 9 is combined with one equivalent of MgCl2 etherate and the fine crystalline precipitate formed is reacted with one equivalent of Grignard reagent (inverse addition). Because it is possibly easier to carry out and not only leads to the desired shift of regioisomer but may also result in an increased yield, it may be advantageous to generate a diaryl magnesium reagent (by precipitating MgBr2 with dioxane) and react it with 9 to obtain 10a. The separation of the regioisomers 10 may also be effected after the etherification step in the end compounds of general formula 1. The variation in the chain length(s) is obtained e.g. by using the Mitsunobu reaction, by using benzylhalides or phenylalkylhalides and preferably using potassium tert-butoxide as auxiliary base and by Reppe reaction using optionally substituted phenylacetylene and subsequent hydrogenation of the Z/E-olefin mixtures produced.
The following are examples of pharmaceutical preparations containing the active substance:
A solution similar to that shown above is suitable for nasal administration in a spray, or in conjunction with a device which produces an aerosol with a particle size preferably between 2 and 6 xcexcM, for administration via the lungs.
Solution for Infusion
A 5% by weight xylitol or saline solution which contains the active substance in a concentration of 2 mg/ml, for example, is adjusted to a pH of about 4 using a sodium acetate buffer.
Infusible solutions of this kind may contain an active substance according to general formula 1 in an amount, based on the total mass of the pharmaceutical preparation, in the range from 0.001 to 5 wt. %, preferably in the range from 0.001 to 3 wt. % and most preferably in the range from 0.01 to 1 wt. %.
Capsules for Inhalation
The active substance according to general formula I in micronised form is packed into hard gelatine capsules (particle size substantially between 2 and 6 xcexcM), optionally with the addition of micronised carrier substances, such as lactose. It can be inhaled using conventional equipment for powder inhalation. Between 0.2 and 20 mg of active substance and 0 to 40 mg of lactose are packed into each capsule.
The Examples which follow serve only to illustrate the invention by way of example without restricting its subject matter.